ORDER OF THE MINISTRY OF HEALTH OF THE RUSSIAN FEDERATION

of August 8, 2018 No. 512n

About approval of Rules of proper practice on work with biomedical cellular products

According to part 3 of Article 6 and part 2 of article 35 of the Federal Law of June 23, 2016 No. 180-FZ "About biomedical cellular products" (The Russian Federation Code, 2016, No. 26, the Art. 3849) and subitem 5.2.207 (7) the Regulations on the Ministry of Health of the Russian Federation approved by the order of the Government of the Russian Federation of June 19, 2012 No. 608 (The Russian Federation Code, 2012, No. 26, Art. 3526; 2013, No. 16, Art. 1970; No. 20, Art. 2477; No. 22, Art. 2812; No. 33, Art. 4386; No. 45, Art. 5822; 2014, No. 12, Art. 1296; No. 26, Art. 3577; No. 30, Art. 4307; No. 37, Art. 4969; 2015, No. 2, Art. 491; No. 12, Art. 1763; No. 23, Art. 3333; 2016, No. 2, Art. 325; No. 9, Art. 1268; No. 27, Art. 4497; No. 28, Art. 4741; No. 34, Art. 5255; No. 49, Art. 6922; 2017, No. 7, Art. 1066; No. 33, Art. 5202; No. 37, Art. 5535; to No. 40, of the Art. 5864, No. 52, of the Art. 8131), I order:

Approve the enclosed Rules of proper practice on work with biomedical cellular products.

Approved by the Order of the Ministry of Health of the Russian Federation of August 8, 2018 No. 512n

Rules of proper practice on work with biomedical cellular products

I. General provisions

1. Rules of proper practice on work with biomedical cellular products (further - Rules) establish general requirements to carrying out preclinical researches, production and quality control of biomedical cellular products (further - BMKP).

2. These rules are applied to cellular lines as to initial materials to production of BMKP, to intermediate products of production of BMKP or the made BMKP if they are included in the initial or processed type into BMKP, are production product which shall pass the subsequent stages of technological processing (further - intermediate product of production of BMKP), or are BMKP intended for production of other BMKP, respectively.

II. Organization of the quality system of production of BMKP

3. BMKP producer (further - the organization) shall make BMKP by the method guaranteeing its compliance to the specification on BMKP <1>, to the requirements established in case of its state registration, to the registration file and the protocol of clinical trial.

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<1> Article 7 of the Federal Law of June 23, 2016 No. 180-FZ "About biomedical cellular products" (The Russian Federation Code, 2016, No. 25, Art. 3849; the official Internet portal of legal information http://www.pravo.gov.ru, on August 3, 2018) (further - the Federal Law No. 180-FZ).

4. For ensuring compliance of the made BMKP to the requirements established in case of its state registration, to the registration file and the protocol of clinical trial in the organization the quality system of production of BMKP (further - the quality system) providing fulfillment of requirements of these rules and risk management for quality assurance of BMKP shall be created. Efficiency of functioning of the quality system in the organization shall be controlled. The head of the organization and authorized person(s) of the organization are responsible for maintenance and control of the quality system.

5. The quality system shall be based on the following principles:

a) the made BMKP meets specifications on BMKP and to the quality indicators established by the regulating documentation on BMKP <2>;

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<2> Part 12 of article 2 of the Federal Law No. 180-FZ.

b) quality of each BMKP series (certain number of BMKP which is made from certain biological and other initial materials in single cycle of production in final packaging and is ready to release) shall be supported and be controlled by division of quality control at all stages and transactions connected with production of BMKP including acceptance of biological and other initial materials, their processing and packaging of BMKP of which receipt of the BMKP series is result (further - engineering procedure);

c) objects, processes and conditions of their implementation exerting impact on quality of BMKP (further - critical objects, processes and conditions of their implementation), are controlled by division of quality assurance with confirmation of their condition;

d) in the organization the efficiency evaluation of production of BMKP according to the procedure, established by internal documentation of the organization is carried out (further - internal documentation);

e) modification of internal documentation regarding requirements to processes, conditions of production and quality control of BMKP is performed for the purpose of improvement of quality of BMKP.

6. The quality system shall provide that in the organization:

a) the issued BMKP series conformed to the requirements established in case of its state registration or, in case of the unregistered BMKP, met specifications on BMKP and to the quality indicators established in the regulating documentation on BMKP (further - BMKP of proper quality);

b) information collection about BMKP and process of its production was performed throughout all production stages of BMKP;

c) transactions on production and quality control of BMKP conformed to requirements of these rules;

d) job responsibilities of heads of the organization and its structural divisions which are taking part in the organization of providing and quality control of BMKP were determined;

e) the measures providing use of biological material, other initial, auxiliary and packaging materials (further - materials for production of BMKP) meeting the requirements of specifications of them and other internal documentation were taken;

e) the head of the organization took the measures providing control of the delivered materials for production of BMKP;

g) control of activities for performance of works by others (third-party) to the organizations was exercised (further - outsourcing);

h) methods of monitoring and control of critical objects, processes and conditions of their implementation were developed and were applied;

i) in case of release of the BMKP series, by consideration of discrepancy of the BMKP series to the requirements established in case of its state registration and (or) the regulating documentation on BMKP and for acceptance of the warning measures in order to avoid emergence of discrepancy to the requirements established in case of state registration of BMKP and (or, in case of the unregistered BMKP) the regulating documentation on BMKP results of monitoring and control of critical objects, processes and conditions of their implementation were used;

j) control of intermediate products of production of BMKP, including unpacked BMKP, control in production process of BMKP was exercised;

k) compliance of techniques, processes, transactions and systems to the requirements established by internal documentation was provided;

l) application of the methods and processes allowing to receive results which correspond to eligibility criterions (further - validation) was provided;

m) it was provided results which correspond to eligibility criterions, in the existing conditions of production (further - verification);

o) enhancement of the quality system and quality of BMKP was performed;

o) assessment of the changes relating to production of BMKP and their approval before implementation was performed;

p) assessment of the changes relating to production of BMKP after their implementation for confirmation of lack of quality degradation of BMKP and the quality system was performed;

c) the division of quality assurance carried out consideration of origins of discrepancy to the indicators of quality of BMKP established by the regulating documentation on BMKP made by BMKP (further - variations), and checks, efficiency evaluations of actions taken adjusting and warning, including with conducting independent, obligatory and periodic checks (further - audit);

r) release of BMKP for clinical application was performed after the certificate by the authorized person of the organization of compliance of BMKP of each BMKP series to requirements identified in case of its state registration or, in case of the unregistered BMKP, the specification on BMKP and to the quality indicators established in the regulating documentation on BMKP;

s) the measures providing quality of BMKP during all expiration date in case of its proper storage and the address were taken;

t) the procedure of internal audits of the quality system regarding its compliance to the requirements established by these rules and internal documents was developed.

7. The head of the organization is responsible for availability of the effective quality system.

8. The organization of the quality system and evaluation procedure of efficiency of its functioning shall be determined by internal documentation. For functioning of the quality system the head of the organization shall provide availability of skilled workers of the organization (further - personnel), rooms, the equipment and technical means.

9. Persons of the organization authorized by her head to exercise control of the quality system, reviews of functioning of the quality system for the purpose of determination of possibility of improvement of quality of BMKP, engineering procedure of production of BMKP and the quality system shall be carried out.

10. The basic principles of risk management for quality of BMKP is establishment of possible negative or undesirable impacts on quality of BMPK (further - risks assessment) which shall be based on scientific knowledge of BMPK, engineering procedure of production of BMKP and experience of production of BMKP.

11. Risk management for quality assurance of BMKP by division of quality assurance includes the systematized processes of assessment, control of parameters of quality of BMKP, and also reviews of risks for quality of BMKP which can be carried out is perspective or is retrospective.

12. For efficiency evaluation of production of BMKP by division of ensuring quality control reviews of quality of BMKP are constituted. The purpose of creation of reviews of quality of BMKP is confirmation of permanency of engineering procedure of production of BMKP and compliance of materials for production of BMKP, intermediate products of production of BMKP, BMKP to the existing specifications on them. The efficiency evaluation of production of BMKP is carried out for the purpose of identification of tendencies on change of parameters of quality of BMKP of the made BMKP series and establishments of possibility of enhancement of BMKP and engineering procedure of productions of BMKP. Results of reviews of quality of BMKP affirm the head of the organization. Frequency of creation of reviews of quality of BMKP is determined by quantity of the made BMKP series, at the same time at least than six BMKP series this on indicators of quality of BMKP are necessary for identification of statistically significant tendencies on change of parameters of quality of BMKP.

13. Reviews of quality of BMKP shall include:

a) the overview of the technological and regulating documentation on BMKP;

b) the overview of the made BMKP series for the accounting period (including approved and the BMKP defective series which did not meet specifications on BMKP and to the quality indicators established by the regulating documentation on BMKP, results of considerations of emergence of the reasons of discrepancy of the BMKP defective series to specifications on BMKP and to the quality indicators established by the regulating documentation on BMKP);

c) the overview of materials for production of BMKP with disaggregation of data on the materials received from new suppliers including the separate overview of chain(s) of delivery(deliveries) of biological materials with assessment of completeness of such overview;

d) the overview of results of control in production process and results of quality control of BMKP;

e) the overview of discrepancies of indicators of quality of BMKP, to the requirements established by the regulating documentation and also the main results of consideration of origins of such discrepancies of indicators of quality of BMKP;

e) the overview of the changes made to engineering procedure and (or) techniques of control;

g) overview of results of testing and monitoring of stability of BMKP and intermediate products of production of BMKP (in the presence);

h) the overview of BMKP of claims, returns and responses connected with quality from the address;

i) the overview of the actions which are carried out adjusting and warning concerning engineering procedure, processing equipment and systems;

j) the overview of compliance of the rooms, the equipment and (or) engineering systems used (involved) in production, quality control and storage of BMKP, to requirements of the Rules, their proper functioning providing the expected results (further - qualification) and confirmations;

k) the overview of assessment of the works (rendered by them services) performed by third parties and their compliance to requirements of these rules;

l) other reviews according to the decision of the head of the organization.

14. In the overview of quality of BMKP the conclusions and conclusions shall be drawn on quality of the BMKP series made for the accounting period, including taking into account the conclusions and conclusions of the previous overview of quality of this BMKP, with development adjusting and the warning actions or conclusion about need of carrying out repeated validation of processes and conditions for their implementation.

15. For quality system efficiency evaluation in the organization by division of quality assurance reviews of the quality system are constituted. Reviews of the quality system are carried out annually for the expired year (further - the accounting period) taking into account data analysis of the previous reviews of the quality system and affirm the head of the organization.

16. Reviews of the quality system shall include:

a) data on reviews of quality of BMKP constituted in the accounting period;

b) the overview of variations for the accounting period;

c) the overview of the arrived claims on quality and responses from the address of the issued BMKP series for the accounting period;

d) the overview of the made changes relating to production of BMKP which exert direct impact on quality of BMKP, for the accounting period;

e) the overview of the adjusting and warning actions taken for the accounting period;

e) the overview of mistakes and corrections of data for the accounting period;

g) the overview of the internal documents published for the accounting period regulating or providing functioning of the quality system;

h) the overview of the carried-out risks assessments for quality of BMKP for the accounting period;

i) the overview of the carried-out podgotovka (retrainings), instructing of personnel for the accounting period;

j) the overview of audits (internal and external) for the accounting period;

k) the overview of results of monitoring of the environment for the accounting period;

l) the overview of the carried-out works on qualification, verification and validation for the accounting period;

m) the overview of results of monitoring of cleaning of the equipment and rooms for the accounting period;

o) the overview of results of control of materials for production of BMKP for the accounting period;

o) other reviews according to the decision of the head of the organization.

17. For quality assurance of BMKP in the organization the complex of the actions directed to creation of conditions for production of BMKP meeting specifications on BMKP and to the quality indicators established by the regulating documentation on BMKP performed during all cycle of production is developed (calendar period of time since the beginning of use of materials for production of BMKP in production before receipt of BMKP, quality control of the made BMKP and its transfer on storage).

18. Process of quality assurance of BMKP consists of the following stages:

a) quality evaluation of BMKP which are in circulation;

b) providing indicators of quality of BMKP, including in the course of development and forming of engineering procedure;

c) development of standards and (or) standard procedures for the quality system;

d) quality control of materials for production of BMKP;

e) functional inspection in production cycle;

e) quality control of BMKP of the made BMKP series;

g) rejection of materials for production of BMKP, intermediate products of production of BMKP and BMKP of inadequate quality;

h) the analysis of claims on quality, responses from the address and returns of the issued BMKP series;

i) control and improvement of engineering procedure;

j) enhancement of the quality system.

19. In the organization the program of providing the quality system shall be implemented. The program of providing the quality system includes:

a) development of internal documentation for forming, maintenance, development and enhancement of the quality system and production of BMKP of quality;

b) assessment of conformity of internal documentation to requirements of Rules and other regulatory legal acts of the Russian Federation;

c) assessment of conformity of the records and data used when ensuring control of cycle of production and quality of BMKP, to requirements of Rules;

d) risk management for quality assurance of BMKP;

e) assessment of the performed changes, consequences of their realization and efficiency;

e) consideration and assessment of variations during development, production and quality control of BMKP;

g) consideration of claims on quality of BMKP and withdrawals of BMKP from the address, returns of the issued BMKP series;

h) assessment of amount and efficiency of the actions which are carried out adjusting and warning;

i) creation of reviews on quality of BMKP;

j) organization of works on qualification, validation and verification;

k) training (retraining), instructing of personnel;

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